Nutraceuticals in the Treatment of Major Depressive Disorder

Abstract

Major depressive disorder (MDD) is the most common mood disorder among adults. Despite the wide use of pharmacological agents by those with MDD, the evidence indicates that only a small fraction of patients benefits, and many individuals using antidepressant therapy relapse. Side effects are numerous with antidepressants, which can be a factor in patient medication compliance. Along with psychotherapy and fine-tuning lifestyle components, another emerging option in treating MDD is the use of bioactive natural products known as nutraceuticals. We present the scientific findings specific to select nutraceuticals (e.g., omega-3 fatty acids, S-adenosyl-methionine, folate-based compounds, and vitamin D) either as a monotherapy or as adjunctive therapy to a pharmaceutical antidepressant, for treatment of MDD. Many studies demonstrate that nutraceuticals result in a decrease in depressive symptoms with fewer side effects as traditional medications and have the potential to improve the result of antidepressants, especially in individuals experiencing resistance to medication. From a therapeutic perspective, a holistic approach incorporating psychotherapy, pharmacological therapy, and lifestyle factors (inclusive of nutraceutical use) appears most logical and could provide for enhanced treatment efficacy.

1. Introduction

According to the National Alliance of Mental Illness (NAMI), one in five US adults experience mental illness each year, with one in twenty experiencing a serious mental illness [1]. Depression and anxiety account for 8.3% and 19.1% of these illnesses, respectively. In the US, mental health diagnoses increased by close to 40% between 2019 and 2023, with the first year of the COVID-19 pandemic accounting for 25% of this increase [1]. Depression can be situational, seasonal, or chronic and recurring, but early detection and treatment can lead to more favorable treatment outcomes.

Pharmacological interventions for mental disorders such as major depressive disorder (MDD) were introduced in the 1950s [2]. While antidepressants are efficacious, nearly 50% of patients remain unable to attain remission [3]. Approximately 11% of the US population take antidepressants [1], and use of these medications have increased yearly over the last eight years [4]. The increasing prevalence of MDD and use of antidepressants, combined with the less than desirable side effects and remission rate, have given rise to the exploration of alternative treatment options.

Beginning in the mid-1990s, a specific class of nutrients referred to as “nutraceuticals” began gaining value in the adjunctive treatment of psychiatric disorders [5]. Today, the nutraceutical business is flourishing at an aggressive rate and is expected by many to become an essential part of the disease care model. To provide some context, the global nutraceuticals market was valued at USD 353 billion in 2022 and is estimated to reach USD 700 billion by 2030 [5].

Nutraceuticals can affect physiological factors that impact the onset of mood disorders including monoamines and brain-derived neurotrophic factor (BDNF) concentrations, neuroinflammation, oxidative stress, and sleep quality [3]. Due to neurobiological effects, neuroprotection, and enhancing re-uptake of inhibited monoamines, it has been emphasized that certain nutraceuticals enhance the effectiveness of medical therapy and alleviate side effects in managing mood disorders [6].

While there are numerous nutraceuticals that are consumed for their supposed mood-enhancing properties, there is a dearth of research to support this practice. Herein, the scientific findings specific to efficacy of nutraceuticals in addressing symptoms of MDD are discussed. Although multiple nutrients are claimed to have efficacy, very few have been studied in a clinical setting. Therefore, the focus of this review is on those nutrients for which a fair number of clinical evaluations have been performed, including omega-3 fatty acids, vitamin D, S-adenosyl-methionine, and folate-based compounds.

We systematically searched PubMed and Google Scholar for articles from 1999 to 2025. Included studies were published, peer-reviewed, and available in English-language journals. The articles examined nutraceuticals and the possible monotherapy and adjunctive effect with pharmaceutical antidepressants, specific to the effect on major depressive disorder.

2. Overview of Major Depressive Disorder

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) separates mood disorders into the following two categories: (1) bipolar and related disorders and (2) depressive disorders.

In terms of relevant research, where nutraceuticals are concerned, MDD is the primary mood disorder studied and is the most common in the adult population, with a prevalence of 8.4% in US adults 18 and older [1]. MDD can occur at any age but is most commonly observed in those between the teenage years and the 30s.

MDD encompasses periods of intense sadness, hopelessness, irritability, feelings of emptiness, and isolation or a loss of interest in otherwise pleasurable activities. Additionally, this disorder is often coupled with somatic symptoms, such as sleep and appetite disturbances, fatigue, and aches and pains [7]. Cognitive disturbances may accompany MDD as well. These symptoms can include difficulty concentrating, trouble remembering things, and a decline in problem solving abilities, along with complications when faced with change [8]. Of the individuals with MDD, it is estimated that two-thirds experience suicidal ideation, while 1–2 out of 30 will commit suicide [9]. MDD can be diagnosed, based on the number of symptoms an individual is experiencing, into the following three severity classifications: mild, moderate, or severe. Due to its complexity, successful treatment of MDD can be difficult.

In its infancy, MDD was thought to be caused mainly by abnormalities in neurotransmitters and receptors, such as serotonin, norepinephrine, and dopamine, but is now considered to have a more complex etiology involving biological, genetic, environmental, and psychosocial factors [9]. Data indicate that there is 30–50% chance of heritability, with 100–200 gene loci identified to likely be associated with MDD [7]. Extreme life stress can also contribute to MDD. Along with monoamine (neurotransmitters), other pathogenic factors can lead to stress-induced changes to the HPA axis, including high levels of glucocorticoids, as well as (thyroid, leptin, and/or estrogen) hormone dysregulation, inflammatory response to oxidative stress (increased inflammatory cytokines including IL-1β, IL-6, IFN-γ, and TNF-α), changes to neurotrophic factors (brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF)), inflammasomes, and structural and functional changes in the brain and its communication with other organs (neuroendocrine–immune axis, gut–brain axis, and liver–brain axis).

Suicide is a significant risk with depression and is the mental health condition most frequently associated with MDD. In fact, a major depressive episode is found in 59–87% of suicide victims in the general population. About two-thirds of individuals with MDD contemplate ending their life, and about 10–15% die by suicide [10]. Unfortunately, many individuals cannot afford medication used to combat MDD. Therefore, it would be advantageous to clarify more affordable and accessible options, such as nutraceuticals, which can be obtained over the counter [11].

3. Treatments for Major Depressive Disorder

3.1. Pharmaceuticals

Pharmacological treatments for MDD can include selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin modulators, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) [9]. Other options include mood stabilizers and antipsychotics, which can be used to enhance the effect of an antidepressant [9]. While SSRIs are the most prescribed medication, no single antidepressant will work for everyone. Antidepressants improved symptoms for approximately 20% of treated patients and prevented relapse in 27% [12]. While antidepressants are efficacious, half of users experience side effects, particularly at the beginning of treatment. Among these side effects are digestive issues (e.g., diarrhea, constipation, and nausea), as well as difficulty urinating, headaches, dizziness, vision issues, and insomnia. Severe side effects include broken bones from falls, heart problems, epilepsy, liver damage, and suicide [12,13]. Patients and providers should work together to monitor side effects to determine whether changes in medication are needed [13].

3.2. Psychotherapy

Psychotherapy, much like pharmacotherapy, is tailored to the individual and may require several sessions to see benefits. Cognitive-behavioral therapy and interpersonal therapy are two of the most common therapeutic approaches for MDD [9]. Cognitive-behavioral therapy focuses on challenging negative thoughts and behaviors, while interpersonal therapy aims to improve relationships and communication skills.

While early research found a combination of pharmacological and psychotherapeutic intervention provided the best chance for remission of MDD [14], more recent meta-analyses indicate that these improvements are minor over the individual intervention types [15]. Combination treatment, however, may increase the likelihood of achieving remission and may also support adherence. In addition, continuing to maintain combination treatment may have the benefits of reducing recurrence and improving quality of life [15].

3.3. Lifestyle Factors

First-line antidepressants are not always effective, and alternative treatment options need to be considered [16]. Although treatment-resistant depression is not well defined, research suggests the condition is quite common and more effective treatment regimens are needed [17]. Aside from pharmacological treatment and psychotherapy, patients and clinicians often look to adjust lifestyle factors as a method of improving mental health. Specifically, regular exercise, consumption of a well-balanced and nutrient-dense diet, improved sleep habits, and a robust spiritual life can help to mitigate many symptoms of affective depressive disorders and lessen or negate the need for pharmaceutical treatment.

3.4. Exercise

Exercise can be both an effective monotherapy and adjunctive treatment for MDD [18]. Along with improving psychosocial functioning [19,20], exercise also reduces inflammation, increases production of endorphins, improves sleep, and enhances self-esteem and social support [21]. Greer (2016) found in individuals diagnosed with non-remitted MDD and currently taking antidepressants that low and high dose exercise habits led to improvements in functioning as well as psychosocial and quality of life measures [22].

3.5. Dietary Intake

A healthy, well-balanced, and nutrient-dense diet has been shown to improve symptoms of depression and anxiety and to decrease the risk of developing either. Diets high in trans fatty acids, high in refined carbohydrates, and low in protein have been associated with MDD [23], which might be attributed to pro-inflammatory properties of refined foods [24]. Increasing consumption of vegetables, fruits, fish, and whole grains has been shown to lower the risk of depression [25], and nutritional imbalances with inadequate intake of omega-3 polyunsaturated fats, vitamin D, folate, iron, and zinc increase the risk for depression [16]. In a systematic review by Swainson of five studies examining various diets, the Mediterranean diet showed the most favorable results, with statistically significant reductions in depression and higher remission rates [26]. Ortega found similar results regarding the Mediterranean diet but also stressed that inclusion of a variety of nutrients and consistent adherence is equally important as the type of diet [27]. Finally, a meta-analysis by Lassale (2018) determined that the Mediterranean diet and avoidance of a pro-inflammatory diet resulted in a reduced risk of depression [28].

3.6. Sleep

There is consensus that a reciprocal relationship exists between sleep, depression, and anxiety. Sleep disruptions can activate the inflammatory response, decrease serotonin production, and affect other factors in the pathophysiology of psychiatric conditions [29]. Over time, the longer sleep is interrupted, the greater the risk of developing or prolonging depression and anxiety [30]. For example, Ngyuyen (2022) followed subjects with depression and anxiety long-term and found higher depression and anxiety scores at baseline predicted lower sleep quality, with this trend continuing at both 9 month and 18 month follow-ups [31]. Sleep quality should, therefore, be prioritized in the treatment and mediation of depression and anxiety.

3.7. Spirituality

Studies have shown that prayer (spirituality) can provide protective factors from depression [32]. These practices can decrease activity in the sympathetic nervous system while increasing parasympathetic activity, creating a calm and relaxed state [33]. Additionally, prayer can complement treatment progress, especially when the method is aligned with one’s values and beliefs [34]. Boelens (2012) found that women engaging in six weekly 1 h prayer sessions for one month had decreased symptoms of depression even at a one-year follow-up [35]. Rickhi (2011) conducted an 8-week study with subjects either implementing a home-based spirituality teaching program or being placed on a waitlist that would start the spirituality teaching program at week 9 [36]. At the 8-week mark, depression severity improved significantly more in the active group as did remission rates, which endured throughout the 24-week period. These findings suggest that spirituality or prayer, when tailored to an individual’s beliefs, can be a positive support to other MDD treatment protocols.

4. Nutraceuticals for Treatment of MDD

Doctor Stephen DeFelice (2003) defines a nutraceutical as a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease [37]. Nutraceuticals were introduced several decades ago to address nutrient deficiencies associated with mental health, to support the effects of pharmaceutical agents, and to provide options for individuals not yet open to taking medication or those with very minor severities of depression, anxiety, etc. [5]. Although not regulated in the same manner as pharmaceuticals, nutraceuticals typically have far fewer side effects compared to pharmaceutical antidepressants and are thought to be an avenue for titrating off prescribed medications [38]. Although current evidence is promising for treating MDD with the limited group of nutraceuticals discussed herein, further clinical research is needed to fully understand their effects, establish optimal dosing, and explore potential combinational usage.

In several trials, the nutraceuticals that have been scientifically tested as an adjunctive therapy for MDD include omega-3, S-adenosylmethionine (SAMe), vitamin D, and L-methylfolate [5,39]. Other agents examined include creatine, curcumin, N-acetyl cysteine (NAC), and pre- and probiotics. However, only a few studies have been conducted, and these nutraceuticals lack consistency in research results.

Juneja (2024) wrote a literature review on creatine supplementation in depression and determined that larger sample sizes, uniformity in methodologies, and further dose–response trials are needed to determine creatine’s effects [40]. Curcumin studies similarly lack adequate sample sizes and randomly controlled trials. Wang’s (2021) meta-analysis found (1) no effect on depressive symptoms, (2) too few small studies included and were underpowered, and (3) the dosage of curcumin in clinically depressed patients was larger than the patients with subclinical depression. Clinical depression has more severe symptoms, and those with mildest clinical effects receive the smallest benefit; (4) all the patients with clinical depression were treated with antidepressants and curcumin at the same time, while patients with subclinical depression were only treated with curcumin [41]. Randomly controlled NAC trials are also limited, and a meta-analysis concluded that NAC supplementation, while promising for its adjunctive use in schizophrenia, lacked efficacy in MDD [42]. Finally, pre- and probiotics have been studied in this area due to findings that the gut microbial profile in individuals with MDD is different compared to healthy individuals, but additional trials are needed to address species, age, diet, and variations in medication use [43]. As previously mentioned, numerous nutraceuticals are touted to benefit mental health, but only a few (omega-3, SAMe, folate, and vitamin D) currently have sufficient scientific support to warrant consideration. These are discussed in more detail below.

4.1. Omega-3 Fatty Acids

Although there are several types of omega-3 fatty acids, the three most prevalent include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA). Of these, ALA is considered essential because the body cannot produce ALA and it must be acquired from food or supplemental forms (note: both EPA and DHA can be synthesized from ALA but due to low conversion efficiency, it is recommended that both are consumed). These polyunsaturated fatty acids (PUFAs) are found in fish and other seafood, particularly salmon and mackerel, but are also found in plants such as flax and chia seeds, and they are widely available in supplement form. The Western diet has evolved in such a way that many individuals are highly deficient in omega-3 fatty acids in favor of omega-6 fatty acids [44]. Omega-3s have beneficial antioxidant, anti-inflammatory, and antithrombotic effects. This knowledge has been an impetus behind researching the relationship between omega-3 fatty acids and mood disorders, as depression is associated with a chronic, low-grade inflammatory response, as well as activation of the compensatory anti-inflammatory reflex system [45]. Epidemiologic data implicate omega-3 fatty acid deficiencies in many mental illnesses [44]. A longitudinal study found that the ratio of 6 to 3 PUFAs is positively associated with mood disorders in young individuals at ultra-high risk [46].

EPA and DHA have both been demonstrated to play a role in brain function and development. Total omega-3 fatty acids, as well as EPA and DHA, are lower in individuals with depression [47]. Omega-3 fatty acids have similar functionality to pharmaceutical antidepressants, as both target inflammation and oxidative stress. Antidepressants target inflammation by decreasing levels of pro-inflammatory cytokines, specifically IL-6 and TNF-α, while increasing the levels of the anti-inflammatory cytokine IL-10 [48]. Omega-3s target inflammation through a variety of mechanisms, including leukocyte hemotaxiss, a part of the body’s immune response [49].

4.1.1. Omega-3 Fatty Acids Animal Studies

One mechanism by which omega-3 fatty acids may improve symptoms of MDD is by altering the activation of the hypothalamic–pituitary–adrenal axis (HPA axis). The HPA axis refers to a chemical messenger system in both animals and humans that facilitates and regulates neurobiological response to stimuli in the environment, shifting protective mechanisms and aiding in the body returning to homeostasis [50]. Diet deficiencies of omega-3 fatty acids observed in rodent studies resulted in a decrease in glucocorticoid receptors and elevated corticosterone secretion due to stress; both outcomes were improved by addition of omega-3 fatty acids [51].

Other research has focused on the role that omega-3 fatty acids play in brain function. Rats fed omega-3 PUFA-deficient diets were found to have altered dopaminergic neurotransmission within the frontal cortex, as well as the nucleus accumbens, an area of the brain that plays a vital role in cognitive and affective functioning [52,53,54]. Rats fed diets lacking DHA subsequently experience lower levels of DHA in brain lipids, with various changes in brain function, including changes in learning and memory, responses to stimuli, and nerve growth factor [55].

Alterations in behavior related to depression were also studied [56,57,58]. Of note, DeMar (2006) found that this type of DHA deprivation showed an increase in depression and aggression test scores in male rat pups [56]. These animal studies demonstrate that dietary levels of omega-3s are strongly related with depressive behaviors.

4.1.2. Omega-3 Fatty Acids Monotherapy Clinical Studies

The omega-3 fatty acids EPA and DHA are of scientific interest due to their potential link to psychiatric health. Although they differ in bioactivity, EPA and DHA share anxiolytic and antidepressant properties [59]. Unlike other nutraceuticals, there are a plethora of randomly controlled trials, systematic reviews, and meta-analyses. However, conclusions from these studies are conflicting, and it is likely, as with most nutraceuticals, that certain individuals are responders to treatment while others are not. For example, a meta-analysis suggested that EPA has a greater effect on symptoms than DHA, regardless of use as a monotherapy or adjunctive therapy [60]. In contrast, a separate literature review found very low certainty in the literature and opined that omega-3 fatty acids have no significant effect on MDD [61].

Depression not only manifests emotionally and behaviorally but also physically through inflammatory responses. Mischoulon (2022) conducted a dose-finding study on subjects with MDD, a body mass index > 25 kg/m², and plasma high-sensitivity C-reactive protein hs-CRP ≥ 3.0 mg/L [62]. Subjects were randomly assigned 1 g, 2 g, or 4 g EPA or a placebo daily for 12 weeks. After 12 weeks, median plasma hs-CRP levels decreased in a dose-dependent manner with the three EPA dosages compared to a minimal decrease in the placebo group. However, no significant changes were found in IL-6 or LPS-stimulated TNF. While all EPA groups displayed sustained improvement in depressive symptoms through the 12 weeks as assessed by the Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30), the results showed the highest response rate in the 4 g per day group, with a 64% improvement at 12 weeks. These findings are promising and deserve attention.

Marangell (2003) also studied monotherapy of omega-3 fatty acid using only 2 g DHA daily compared to a placebo. Response was defined a priori as a ≥50% reduction in the score on the Montgomery–Åsberg Depression Rating Scale. Thirty-five participants were evaluable; eighteen received DHA, and seventeen received placebo. The response rates were 27.8% in the DHA group and 23.5% in the placebo group. The difference in response rates among groups did not reach statistical significance [63]. This trial failed to show a significant effect of DHA monotherapy in subjects with major depression at the dosage of 2 g daily. Another consideration that could be clarified in future studies is the potential differences in efficacy for EPA and DHA. EPA exhibited greater efficacy when compared to DHA in [64], but no difference was observed in [65].

4.1.3. Omega-3 Fatty-Acids Adjunctive-Therapy Clinical Studies

While monotherapy use of omega-3 fatty acid shows some promise in alleviating depressive symptoms, it may also be advantageous as an adjunctive therapy to pharmaceutical antidepressants. The Omega-3 Fatty Acid Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the APA, advises that patients with mood, impulse-control, or psychotic disorders should consume 1 g EPA + DHA per day. A supplement may be useful in patients with mood disorders, with a wide range of dosages (1–9 g per day) [66]. Jazayeri (2008) compared the therapeutic effects in MDD of 1000 mg EPA + fluoxetine placebo, 20 mg fluoxetine + EPA placebo, and a combination of 1000 mg EPA + 20 mg fluoxetine. Depression was evaluated via the Hamilton Depression Rating Scale (HAM-D) and subjects were assessed every two weeks [67]. The results showed the fluoxetine + EPA was significantly better than fluoxetine or EPA individually. Fluoxetine and EPA monotherapies appeared to be equally effective in controlling depressive symptoms. Response rates were a 50%, 56%, and 81% decrease in the fluoxetine, EPA, and combinations groups, respectively. In another adjunctive study, Gertsik (2012) evaluated the effectiveness over 8 weeks of 900 mg EPA + 200 mg DHA + 100 mg other omega-3 fatty acids + 20 g citalopram versus antidepressant monotherapy control, 2 g olive oil + 20 g citalopram [68]. Positively, this study also included a one-week, single-blind, and placebo run-in phase to assess for any placebo effects in the HAM-D scores (used to evaluate changes in depressive symptoms) from baseline testing. The results indicated that beginning at 4 weeks of adjunctive treatment with citalopram and omega-3, a significantly greater reduction in HAM-D scores was found compared to citalopram treatment alone. However, there were no changes in plasma CRP or 24 h urinary cortisol levels over the study period.

The research reviewed here has strong indications that EPA, as an adjunctive therapy, is promising, but dosing could be dependent on individual factors, such as length of time since diagnosis of depression, inflammatory status, and current intake of omega-3. When referencing the cited articles, dosages vary between 0.9 g and 9 g per day, both in monotherapy and adjunctive uses. It could also be suggested that the addition of a placebo run-in in studies could be greatly useful in clarifying results.

4.2. S-Adenosylmethionine (SAMe)

SAMe is a compound found naturally in the body that acts as a methyl donor in the production and breakdown of chemicals, such as serotonin, dopamine, noradrenaline, and melatonin, within the brain [69]. Higher concentrations are found in the liver and the adrenal and pineal glands [70]. SAMe is not readily found in food sources and, therefore, not technically a nutraceutical by definition. However, SAMe is marketed and sold in the United States as a dietary supplement and has previously been described as a nutraceutical in previous research. Disruption of the methylation cycle leads to lowered levels of SAMe and elevated homocysteine, which negatively affects the balance of the neurotransmitter systems [71]. This imbalance contributes to depressive symptoms by increasing oxidative stress and homocysteine levels [71]. Unlike many nutraceuticals that have solely been researched as an adjunctive treatment, SAMe has been studied as a monotherapy for MDD, specifically in individuals considered non-responders to traditional antidepressants. It is important to note that SAMe may exacerbate mania symptoms in bipolar disorder and should, therefore, be avoided, even during depressive episodes [72].

4.2.1. SAMe Animal Studies

There have been limited animal studies to date on the effects of SAMe on depression. Tillman (2019) studied the effects of SAMe in the Flinders Sensitive Line rat model, which shares similarities with humans in terms of depression and reduced liver SAMe concentrations, and found that SAMe did not exhibit antidepressant effects [73].

Benelli (1999) studied anhedonic behavior in castrated rats and whether different dosages of SAMe were as effective a treatment as imipramine, which is known to increase levels of serotonin and norepinephrine in the brain [74]. Anhedonia is a classic symptom of depression defined by lack of interest, enjoyment, or pleasure. This was measured by sucrose intake, the open-field test (OFT), and the place preference test. After three weeks of exposure to chronic mild stress (modifications of light/dark cycle, food and water availability, and housing conditions), sucrose consumption was reduced and animals were assigned to one of the following five treatments: (1) 100 mg SAMe, (2) 200 mg SAMe, (3) 300 mg SAMe, (4) 10 mg imipramine (a tricyclic antidepressant), or (5) 1 mL vehicle. Increased sucrose consumption (a measure of anhedonia) was observed following injection of SAMe, as well as a rapid reversal of anhedonia-like behavior demonstrated by the OFT and place-preference testing. Due to its role in serotonin production and breakdown, some researchers believe the baseline serotonin levels may be a determining factor in the effect SAMe has, postulating that this nutraceutical may be quicker acting and more potent when serotonin levels are low.

4.2.2. SAMe-Monotherapy Clinical Studies

Sarris (2014) compared individuals randomly assigned to SAMe (1600–3200 mg/day) as a monotherapy, escitalopram (10–20 mg/day), or placebo for 12 weeks after a wash out period [75]. Depression was measured using the Hamilton Depression Rating Scale (HAMD-17) at baseline and then again every two weeks during treatment. SAMe outperformed escitalopram and placebo in reducing the HAMD-17 score, although significance was not reached. At the 12-week endpoint, remission rates were 34% for SAMe, 23% for escitalopram, and 6% for placebo.

In a more recent study, 800 mg SAMe per day was compared to placebo in an 8-week double-blind, randomized trial [76]. Despite a high placebo response rate of 53%, SAMe had a greater reduction from baseline to week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS), though significance was not reached. These studies elucidate that even at varying doses, SAMe has not been shown to be an effectual monotherapy for MDD.

4.2.3. SAMe-Adjunctive-Therapy Clinical Studies

Sarris (2018) also conducted an 8-week study for SAMe adjunctive therapy in patients diagnosed with MDD [77]. The study compared 800 mg SAMe with antidepressant to a placebo with antidepressant. Outcomes were measured using the MADRS and analyzing one-carbon cycle nutrients, pertinent single-nucleotide polymorphisms (SNPs), and BDNF. The results showed a significant overall reduction in MADRS scores over time, but no significant between-group difference was observed, nor were significant differences found for any secondary measures.

In an earlier study, Papakostas (2010) evaluated a higher dose of SAMe (800 mg/twice daily) for 6 weeks as an adjunct therapy to antidepressants with patients considered non-responders to serotonin reuptake inhibitors (SRIs) [70]. When compared to placebo + SRI, the SAMe + SRI group demonstrated a higher HAM-D response along with higher remission rates. Response rates for SAMe treatment versus placebo were 36.1% versus 17.6%, respectively and remission rates were 25.8% versus 11.7%, respectively.

While SAMe does not have notable effects as a monotherapy, it does show an ability to decrease depressive symptoms as an adjunctive therapy to antidepressants Considering the span of dosages in the cited studies, which were between 100 mg and 3200 mg, future research may benefit by looking more into baseline levels of SAMe prior to beginning the intervention.

4.3. Folate

Folate is a B-vitamin and essential micronutrient necessary in the synthesis of dopamine, serotonin, and epinephrine. Lower levels of folate have been found in mental health disorders such as schizophrenia and MDD and may also contribute to the severity of such disorders [71]. Folate deficiency is associated with a metabolic imbalance resulting in decreased levels of SAMe; thus, these two nutraceuticals are often taken together. Along with its tie to mental disorders, folate deficiency has also been linked to resistance to pharmaceutical agents [78].

4.3.1. Folate Animal Studies

In a 6-week study, Zhou (2020) compared the following four groups of rats: (1) control, (2) chronic unpredictable mild stress (CUMS), (3) CUMS + folic acid, and (4) CUMS + citalopram [79]. The results showed a significant increase in serum folate and a reduction in serum homocysteine in the CUMS + folic group; citalopram did not influence these. Sucrose preference test (SPT), exercise distance, and standing times were all improved in the CUMS + folic acid group, but CUMS + citalopram group performed better. Monoamine neurotransmitters (5-HT, dopamine, norepinephrine) were not affected in either the folic acid or CUMS group, but all three were higher in the citalopram group. Folic acid significantly decreased IL-6 in serum and brain tissue, as well as the level of BDNF in serum but not brain tissue. No significant difference between folic acid and CUMS groups in b-EP was found, leading researchers to express the need for more studies on the relationship between folic acid and b-EP.

Réus (2018) conducted a rodent study that looked at treating depression stemming from both early- and late-life stress [80]. Early-life stress was brought on by maternal deprivation (MD) and late-life stress was induced using the chronic mild stress (CMS) protocol. Rats were treated with either folic acid, NAC, or omega-3 fatty acids. Depressive behavior was assessed by evaluating immobility in the forced swimming test (FST)and oxidative stress in the brain was also measured. The results showed a decrease in immobility time in stressed rats treated with folic acid compared to untreated stressed rats. Rats subjected to MD and treated with NAC, folic acid, and omega-3s showed a decrease in immobility time compared with MD rats treated with water. Malondialdehyde (MDA), a biomarker of lipid-specific oxidative stress, was reduced in the stressed rats treated with folic acid when compared to untreated stressed rats.

4.3.2. Folate-Monotherapy Clinical Studies

Low folate levels have been associated with depression and lengthened durations due to its role in the production of serotonin, dopamine, and norepinephrine. Studies on folate as a monotherapy are rare, but Shelton (2013) performed a study focused on both monotherapy and adjunctive therapy with folate [81]. Of the 52 subjects in the monotherapy group, there was a 7.7-point decrease in the Patient Health Questionnaire (PHQ-9), with nearly two-thirds of subjects reporting a positive response to treatment and half reporting remission in their depressive symptoms. Reynolds (2015) conducted a study on folate as a monotherapy, and although the sample was small, n = 8, found that this group responded with a mean reduction in MADRS scoring of 45% [82]. Response was defined as a 25% reduction in MADRS scoring, concluding a positive outcome.

4.3.3. Folate-Adjunctive-Therapy Clinical Studies

Not only are low folate levels correlated with depression, but individuals with decreased folate are less likely to respond to traditional antidepressants. Coppen and Bailey (2000) designed a 10-week study comparing 500 mg folic acid + 20 mg fluoxetine to placebo + 20 mg fluoxetine in groups of men and women [83]. Depressive symptoms were measured at baseline and every 2 weeks using the Hamilton Rating Scale (HRS), and plasma folate was measured at baseline, 4 weeks, and 10 weeks. All groups experienced a decrease in HRS scores, with the women in the folic acid + fluoxetine group having the most significant decrease. All patients in the folic acid + fluoxetine group had significantly increased levels of plasma folate.

Ginsberg (2011) compared two dosages of folic acid paired with an antidepressant and a control group of subjects using antidepressant monotherapy [84]. Subjects had a primary diagnosis of MDD and had been on their usual antidepressant for at least 60 days. The Clinical Global Impression-Severity scale (CGI-S) was used to evaluate the response to pharmacologic medication. In subjects with less severe depression, results showed 18.5% of the folic acid + antidepressant group experienced an improvement in CGI-S scores, compared to 7.04% of the monotherapy group. In those with more severe depression, 40% of the folic acid + antidepressant group saw an improvement in CGI-S scores, compared to 16.3% in the monotherapy group.

As with the previous nutraceuticals mentioned, folate produces positive results in depressive symptoms when used as an adjunctive treatment, but individuals with less severe symptoms do not experience the same robust effects. Considering the relationship between folate and SAMe, it would be worthwhile to study the pairing of these agents. Dosages in the cited studies range widely, from 7.5 mg to 500 mg of folate.

4.3.4. Other B Vitamins

While much research has focused on folate alone, it has been put forth that a combination strategy to vitamin B use may be more effective due to the differing actions of the B vitamins, suggesting that other B vitamins may also play an important role in mitigating the pathology of depression [85]. In one RCT, vitamin B6 plus magnesium was found to reduce depression scores from moderate to normal over the course of 8 weeks [86], and a large cross-sectional study found an association between lower B6 intake and increased risk of depression and anxiety [87]. Vitamin B6 has also been found to reduce self-reported anxiety and induced a trend toward reduced depression, which aligns with these two mental health conditions considering they are intrinsically related and overlap in GABAergic neurochemistry [88]. B vitamins may improve MDD via actions in neurotransmittors, as well as decreasing levels of inflammatory cytokines [89,90]. In addition to folate (vitamin B9), deficiencies of vitamins B6 (pyridoxine) and B12 (cobalamin) have previously been associated with various neurological disorders including depression [91]. Combination B6, B9, B12 enhanced antidepressive response of individuals on citalopram over 1 year compared to a placebo, as determined by Montgomery–åsberg Depression Rating Scale (MADRS) [92]. In a systematic review of 20 randomly controlled trials, the combination of folic acid, B1, B12, and vitamin D significantly decreased depressive scale scores by enhancing the efficacy of antidepressants and was also found to be effective as a monotherapy [93]. In one longitudinal study of adults over the age of 50, it was observed that those with a deficient-low B12 status had a 51% increased likelihood of developing depressive symptoms over 4 years [94]. A relationship was also found between a healthy dietary pattern and a reduced risk of depression via increased serum levels of folate and vitamin B12 [95]. Additionally, consuming high levels of B8 (particularly for women) has been associated with lower likelihood of depression [91]. However, conflicting literature also exists. In a systematic review and meta-analysis, there was found to be no effect of vitamin supplementation on depressive symptoms; neither as adjunctive nor monotherapy [96]. More research is needed to determine whether B vitamins in addition to folate or combinations of B vitamins could provide a therapeutic response for MDD.

4.4. Vitamin D

While vitamin D has a known role in calcium metabolism, it may also be involved in brain and nervous system health and disease [97]. Reduced levels of vitamin D have also been reported in many psychiatric disorders, namely depression and anxiety. Touted as a neuro hormone, vitamin D has two main forms, D₂ (ergocalciferol) and D₃ (cholecalciferol). It is involved in the synthesis, release, and regulation of neurotransmitters such as serotonin and may also affect other hormones such as oxytocin, although supporting research is scarce. Vitamin D₃ has been shown to be more active and superior to D₂ in raising and maintaining serum vitamin D levels [98]. Vitamin D₃ is available naturally in many food sources such as eggs and fatty fish, while vitamin D₂ is mainly found in mushrooms [99]. However, getting an adequate amount through food can be difficult, and many individuals do not obtain the needed sunlight exposure (especially considering the use of high SPF sunscreens) to allow for the conversion of vitamin D through the skin. Thus, vitamin D supplements are viewed by many as beneficial. However, it is not clear whether adjunctive treatment is effective in alleviating depressive symptoms or contributing to remission [100].

Reduced levels of vitamin D have been reported in many psychiatric disorders, namely depression and anxiety. Vitamin D has a known role in calcium metabolism, but it also affects brain and nervous system health and disease [97].

The relationship of vitamin D and seasonal effects on mental health, specifically depression in the form of seasonal affective disorder is also a topic of interest [101]. Seasonal affective disorder differs from MDD in that it originates in fall or winter months when sun exposure is lower, and typically remits as the season changes to spring or summer [102].

4.4.1. Vitamin D Animal Studies

Vitamin D supplementation (100–10,000 IU daily) improved anxiety and depression in rats exposed to unpredictable chronic mild stress (UCMS), as assessed via the following three behavioral tests: OFT, elevated plus maze (EPM), and FST. Brain tissue oxidation (MDA) and neuroinflammation (IL-6) were also decreased following UCMS in the rats treated with vitamin D compared to those that were not [103]. In a separate study, anhedonic behavior assessed via SPT was lower in male rats undergoing CMS that were injected with 10,000 IU vitamin D daily compared to CMS and no treatment, indicating decreased depression. However, the study saw no improvement to anxiety during OFT with treatment [104].

Al-Ramadhan (2023) explored vitamin D as both a monotherapy and adjunctive therapy [105]. Alterations in behavioral markers of depression were assessed using the following five experimental groups: (1) control group, (2) the CUMS group, (3) the CUMS group receiving vitamin D (10 mg/kg), (4) the CUMS group receiving fluoxetine (5 mg/kg), and (5) the CUMS group receiving both vitamin D and fluoxetine. Baseline testing was performed in behavioral tests (EPM, FST, OFT, tail-suspension test (TST), and SPT). After three weeks, significant changes were observed in vitamin D + CUMS group in the EPM and TST. In both the vitamin D + fluoxetine + CUMS and the vitamin D + CUMS groups, the vitamin D treatments had antidepressant effects in the FST, OFT, and SPT tests. In summary, this study found that a combination of fluoxetine and vitamin D yielded better results than either agent on its own.

4.4.2. Vitamin-D-Monotherapy Clinical Studies

In an 8-week double-blind study on the effects of high-dose vitamin D on mild to moderate depression, subjects were assigned either vitamin D₃ (50,000 IU/2 weeks) or placebo and were assessed pre- and post-treatment using the Beck Depression Inventory (BDI-II) and blood analysis [106]. At 8 weeks, serum concentrations of vitamin D increased significantly in the vitamin D group by approximately 40 nmol/L compared to placebo approximately 5 nmol/L. BDI-II scores decreased in both groups; however, the vitamin D group was significantly lower than placebo. There were no significant differences between treatment and placebo for oxytocin, serotonin, intact parathyroid hormone post-treatment. These findings suggest that while vitamin D improved mood, it did not impact hormones or neurotransmitters.

In a 6-month female only study, Choukri (2018) studied the effect of vitamin D on depressive symptoms, anxiety, flourishing, and positive and negative mood during the winter months in New Zealand [107]. Subjects were randomly assigned either 50,000 IU of vitamin D or placebo once per month. The vitamin D group showed a significant increase in serum vitamin D. Serum vitamin D levels in the placebo group declined over the study, which was expected due to seasonal changes. No significant differences, however, were found between the vitamin D and placebo groups in any outcome measures of depression assessed using the Center for Epidemiologic Studies Depression Scale (CES-D), the Hospital Anxiety and Depression Scale (HADS), and the Flourishing Scale.

4.4.3. Vitamin D Adjunctive-Therapy Clinical Studies

In an 8-week study, Khoraminya (2013) assessed vitamin D adjunctive-therapeutic effects using the 24-item Hamilton Depression Rating Scale (HAM-D) and 21-item Beck Depression Inventory (BDI) post-treatment with either 1500 IU vitamin D daily + 20 mg fluoxetine or 20 mg fluoxetine + placebo in patients with MDD [108]. The results showed that serum 25(OH)D increased significantly in the vitamin D group following treatment, and depression severity improved significantly more in the vitamin D group from the fourth week of treatment.

In a recent double-blind, randomized controlled study with MDD patients, Zhao (2024) used 1600 IU vitamin D as an adjunctive therapy to existing antidepressant regimens on clinical symptoms, as well as its potential preservation effects on brain structural and functional connectivity [109]. Following 7 months, serum vitamin D levels increased from baseline to follow-up in the group receiving vitamin D with no change in the placebo group. Clinical symptoms in both groups improved scores on the Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAMA), although no significant group-by-time interactions were observed. White-matter integrity and functional network connectivity results revealed decreased fractional anisotropy (FA), a quantitative biomarker of white-matter integritys in the right inferior fronto-occipital fascisulus (IFOF) of the placebo group with no change in the vitamin D group. There was a significant group-by-time interaction effect on functional connectivity between the right frontoparietal network (rFPN) and medial vestibular nucleus (mVN). This study found that adjunctive vitamin D improved clinical symptoms of depression and shows the potential to protect white matter in the brain.

The studies reviewed here indicate that vitamin D is a promising adjunctive therapy to antidepressants, but, as with the prior supplements reviewed in this paper, treatment as a monotherapy agent does not have significant effects on depressive symptoms. Dosages in the cited papers ranged widely, from 100 IU daily of vitamin D to 50,000 IU over the course of 2 weeks. Considering such a large dosage range, future research may focus on determining a more tightly defined dose range, as well as treatment period.

4.5. Summary of Nutraceuticals for MDD

When considering the collective data summarized in

Table 1. Relevant clinical trials of nutraceuticals as a monotherapy and/or adjunct therapy for depression.

Nutraceutical	Dose (Daily Unless Otherwise Specified)	Duration	Treatment	N	Outcome	Source
Omega 3/PUFAs	1 g EPA vs. 1 g DHA vs. placebo	12 weeks	Monotherapy	62	Small portion of EPA group improved HDRS scores	[62]
	DHA 2 g vs. placebo	6 weeks	Monotherapy	35	No significant improvement in MADRS scores	[61]
	EPA 1 g, 2 g, or 4 g vs. placebo	12 weeks	Monotherapy	45	All EPA groups improved in IDS-C30 scores	[60]
	1 g EPA + fluox vs. 1 g EPA mono vs. fluox only	8 weeks	Fluoxetine 20 mg/day	48	EPA + fluoxetine group significantly improved HAM-D scores	[65]
	1.8 g EPA	8 weeks	Citalopram 20–40 mg/day	32	Significantly greater reduction in HAM-D in omega-3 + citalopram group	[66]
SAMe	1600–3200 mg vs. escitalopram vs. placebo	12 weeks	Monotherapy 10–20 mg escitalopram	102	SAMe outperformed escitalopram + placebo in HAMD-17	[73]
	800 mg vs. placebo	8 weeks	Monotherapy	41	SAMe reduced MADRS scores	[74]
	800 mg SAMe + antidepressant	8 weeks	Current antidepressant	107	No significant results in MADRS scores, SNPs, or BDNF	[75]
	1600 mg vs. placebo	6 weeks	SSRI or SNRI	42	SAMe + antidepressant out-performed placebo in HAM-D & increased remission	[68]
Folate	7.5 or 15 mg	3 months	Monotherapy & adjunctive	52 Mon 502 Adj	PHQ-9 scores decreased	[79]
	0.5 mg vs. placebo	10 weeks	Fluoxetine 20 mg/day	109	HRS scores in folic acid + fluox significantly decreased	[81]
	7.5 mg or 15 mg + SSRI or SNRI vs. SSRI or SNRI monotherapy	60 days	Current SSRI or SNRI dose	242	CGI-S improved in folic acid + antidepressant group	[82]
Vitamin D	50,000 IU/2 weeks vs. placebo	8 weeks	Monotherapy	56	Vitamin D improved BDI-II	[92]
	50,000 IU/month vs. placebo	6 months	Monotherapy	71	No significant differences	[93]
	40,000 IU D3 per week vs. placebo	6 months	Monotherapy	230	No significant effect of Vitamin D MADRS, BDI-II, HADS or SPAQ	[96]
	1500 IU vs. placebo	8 weeks	Fluoxetine 20 mg/day	40	Vitamin D + fluoxetine improved HDRS & BDI	[94]
	1600 IU D3/day + antidepressant vs. placebo + antidepressants	7 months	Regular dose of antidepressant	72	HAM-D & HAMA scores improved in both groups	[95]

, it appears that select nutraceuticals may share similar mechanisms of action as available pharmaceutical treatments used for MDD. The research to date suggests that nutraceuticals may be more efficacious as an adjunct to pharmaceutical therapies than as monotherapies. Omega-3 fatty acids were shown to be effective in reducing depressive symptoms, both as a monotherapy and adjunct to pharmaceutical therapies; however, EPA was found to be more efficacious when compared to DHA. When used alone, SAMe did not have significant positive results in depression symptoms but can decrease symptoms when used as an adjunctive therapy, and the effect can be more robust in individuals with low serotonin levels. Folate as a monotherapy decreased scores on depression scales and decreased depressive symptoms as an adjunctive therapy. B vitamins and vitamin D both carry conflicting results as monotherapies, but both show promise in improving symptoms and enhancing the effectiveness of pharmaceutical interventions.

Positively, the studies reviewed include both animal and human clinical trials; however, the body of research on the subject of nutraceuticals in the treatment of MDD remains sparce and is faced with many limitations. For example, there has been a span of severities of MDD and variations in nutraceutical intervention with regard to nutrient type and dosage, as well as length of intervention, and, therefore, no continuity of length of study treatment or definition of follow-up results. Studies typically ranged from 8 weeks to several months, and, while it may be challenging and costly to do so, future work should consider following subjects for greater than 6 months. It may also be advantageous to consider the lifestyle factors of subjects or incorporating these into studies along with nutraceutical intervention. This could possibly address how, or if, the current lifestyle factors of individuals affect the efficacy of these supplements. Future studies could also benefit by categorizing by sex, age, length of time an individual has suffered with MDD, and severity of MDD.

More research is needed in order for nutraceuticals to be accepted into standard therapeutic practice, specifically as adjunctive therapy with antidepressants. Studies utilizing higher doses of select ingredients are typically met with positive results, therefore there is likely a need to determine dosing recommendations as we see in clinical pharmacokinetic studies. Ideally, nutraceuticals need to be assessed with the same tangible efficacy metrics and attentiveness as are done with FDA approved pharmaceuticals. This would better allow individuals and health professionals to make scientifically based recommendations based on patient needs.

4.6. Prebiotics, Probiotics, and Symbiotics

Although a relatively new player in the world of nutraceuticals and dietary supplements, agents that impact the gut microbiome have become extremely popular in recent years, with the microbiome being another potential therapeutic target for MDD, as it interacts with the brain via the gut–brain axis. Many studies have identified a significant relationship between the gut microbiome and MDD, with differences in beta diversity and increased Proteobacteria and Enterobacteriaceae, in particular [43,110]. The gut microbiome, particularly during dysbiosis, may disturb multiple potential MDD pathways including neurotransmitters, stress response in the HPA axis, brain-derived neurotrophic factor (BDNF) levels, and inflammatory cytokine levels [43], as seen in Figure 1. Supplementing prebiotics (nondigestible sugars metabolized by certain microorganisms in the gut microbiome), probiotics (specific strains of microorganisms such as Lactobacillus and Bifidobacteria), or symbiotics (combination of pre- and probiotics) may ameliorate the negative conditions contributing to MDD. Multiple meta-analyses have shown improvements in depression scores, principally for probiotics, with varying degrees for probiotics and symbiotics when compared to placebo [43,110,111]. Despite these findings, there is insufficient data on how these agents perform as a mono- or adjunct therapy for the treatment of MDD in comparison to pharmaceuticals, and, therefore, no recommendation is being made at this time.

5. Conclusions

MDD is a serious mental disorder affecting a substantial part of the population and prevalence is on the rise. Accepted treatments include psychotherapy and antidepressants, but the latter carry many undesirable side effects, and some individuals find they cannot tolerate them. Lifestyle changes, such as exercise, diet, sleep, and spirituality, could also be first-line defense strategies, as well as preventive measures. Nutraceuticals can provide support for MDD, with many nutrients incorporated into the diet through food sources, with increases in dosing more easily provided in supplemental form. Nutraceuticals have the most potential as adjunctive agents to antidepressants in improving depressive symptoms and can possibly lower inflammatory biomarkers. From a therapeutic perspective, a holistic approach inclusive of lifestyle modification (spiritual growth, adequate sleep, exercise, and nutrient-dense diet), psychotherapy, pharmaceutical intervention, and nutraceutical support should be considered.